分化誘導剤の作用機構の解析と治療効果の検討

• Project/Area Number: 12217160
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Shimane University (2004); Research Institute for Clinical Oncology, Saitama Cancer Center (2000-2003)
• Principal Investigator: 本間 良夫 島根大学, 医学部, 教授 (70142114)
• Co-Investigator(Kenkyū-buntansha): 粕壁 隆 埼玉県立がんセンター, 研究室・主任研究員 (50152658) ; 山口 ゆり 埼玉県立がんセンター, 研究室・専門研究員 (80166628) ; 角 純子 埼玉県立がんセンター, 研究室・専門研究員 (30161136)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥49,500,000 (Direct Cost: ¥49,500,000); Fiscal Year 2004: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 2003: ¥9,800,000 (Direct Cost: ¥9,800,000); Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 2001: ¥10,200,000 (Direct Cost: ¥10,200,000); Fiscal Year 2000: ¥9,500,000 (Direct Cost: ¥9,500,000)
• Keywords: がん治療 / 分子標的治療 / 分化誘導療法 / 卵巣癌 / interferon-α / cotylenin A / 分化誘導剤 / 細胞分化 / 白血病 / 肺癌 / インターフェロン / 植物ホルモン / サイトカイニン / 急性骨髄性白血病 / 急性前骨髄球性白血病 / cytosine arabinoside / cytidine deaminase / 抗癌剤

Research Abstract

多くの固形癌細胞はinterferon-α単独ではほとんど増殖を抑制しないが、低濃度の白血病分化誘導剤cotylenin Aとの併用により効果的に細胞増殖抑制とアポトーシスを誘導した。しかし正常細胞に対して増殖抑制効果はほとんど示さなかったことから、この併用療法はがん細胞に対し選択性が有ることを示唆した。またこの併用療法はヒト肺癌細胞を移植したヌードマウスにおいて顕著な抗腫瘍効果を示した。この併用療法を臨床応用に向ける一歩として、固形腫瘍細胞に対する効果を網羅的に調べるため、ヒトがん細胞パネルで解析を行なった。その結果、多くの種類の固形癌細胞に有効であったが、特に卵巣癌細胞において効果的であった。検討した卵巣癌細胞株の5株すべてがこの併用療法により相乗的にアポトーシスを誘導し、卵巣癌への臨床応用の可能性を期待させた。そこで患者から採取した癌細胞においても効果的に作用するか検討した。抗癌剤感受性テストをcollagen gel droplet embedded cultureにより評価したが、患者からの卵巣癌細胞も4例中1例を除いて株細胞とほぼ同等の感受性を示した。またこの併用療法はcis-platin耐性細胞に対してもほぼ同等の感受性を示したことから、化学療法が無効となった症例にも有効である可能性が示唆された。この併用療法はヌードマウスに移植した卵巣癌細胞の増殖を顕著な副作用もなく著しく抑制した。以上の結果は、interferon-αとcotylenin Aとの併用療法は卵巣癌への応用の可能性を示唆した。

Research Products

• [Journal Article] Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivatives (2005)
  • Author(s): Adachi, R., et al.
  • Journal Title: J.Lipid Res. 46 Pages: 46-57
• [Journal Article] Nuclear DNA but not controls tumor phenotypes in mouse cells. (2005)
  • Author(s): Akimoto, M., et al.
  • Journal Title: Biochem.Biophys.Res.Commun. 327 Pages: 1028-1035
• [Journal Article] MmTRA1b/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia. (2004)
  • Author(s): Yokoyama, A., et al.
  • Journal Title: Leuk.Res. 28 Pages: 149-157
• [Journal Article] Granulocytic differentiation of leukemic cells with t(9;11)(p22;q23) induced by all-trans-retinoic acid. (2004)
  • Author(s): Iijima, K., et al.
  • Journal Title: Leuk.Lymph. 45 Pages: 1017-1024
• [Journal Article] Induction of differentiation of human myeloid leukemia cells by jasmonates, plant hormones. (2004)
  • Author(s): Ishii, Y., et al.
  • Journal Title: Leukemia 18 Pages: 1413-1419
• [Journal Article] Clinical significance of intracytoplasmic nm23-H1 expression in diffuse large B-cell lymphoma. (2004)
  • Author(s): Niitsu, N., et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 2482-2490
• [Publications] Honma, Y., Ishii, Y., Yamamoto-Yamaguchi, Y., Sassa, T., Asahi, K.: "Cotylenin A, a differentiation-inducing agent, and interferon-α cooperatively induce apoptosis and have an antitumor effect of human non-small cell lung caricinoma cells in nude mice"Cancer Res.. 63. 3659-3666 (2003)
• [Publications] Honma, Y., Ishii, Y., Sassa, T., Asahi, K.: "Treatment of human promyelocytic leukemia in the SCID mouse model with cotylenin A, an inducer of myelomonocytic differentiation of leukemia cells."Leuk Res. 27. 1019-1025 (2003)
• [Publications] Ishii, Y., Sakai, S., Honma, Y.: "Cytokinin-induced differentiation of human myeloid leukemia HL-60 cells is associated with the formation of nucleotides, but not with incorporation into DNA or RNA."Biochim.Biophys.Acta. 1643. 11-24 (2003)
• [Publications] Niitsu, N, Honma, Y, Iijima, K, Takagi T, Higashihara, M, Sawada, U, Okabe-Kado, J.: "Clinical significance of nm23-H1 proteins expressed on cell surface in non-Hodgkin's lymphoma."Leukemia. 17. 196-202 (2003)
• [Publications] Nakamaki, T., Hamano, Y., Hisatake, J., Yokoyama, A., Kawakami, K., Tomoyasu, S., Honma, Y., Koeffler, P: "Elevated levels of cyclin A1 and A(A2) mRNA in acute myeloid leukemia are associated with increased survival."Br.J.Haematol.. 123. 72-80 (2003)
• [Publications] Honma, Y.: "Adenine analogs as potential differentiation therapy agents for acute myeloid leukemia."Drug Development Research. 59. 14-22 (2003)
• [Publications] 本間良夫(分担執筆): "臨床腫瘍学第3版(日本臨床腫瘍学会:編)分担箇所:分化誘導療法"癌と化学療法社. 279-285 (2003)
• [Publications] Ishii, Y, Hori, Y, Sakai, S, Honma, Y.: "Control of differentiation and apoptosis of human myeloid leukemia cells by cytokinins and cytokinin nucleosides, plant redifferentiation-inducing hormones"Cell Growth and Differentiation. 13. 19-26 (2002)
• [Publications] Niitsu, N, Higashinara, M, Honma, Y.: "The catalytic DNA topoisomerase II inhibitor ICRF-193 and all-trans retinoic acid cooperatively induce granulocytic differentiation of acute promyelocytic leukemia cells : candidate drugs for chemo-differentiation therapy against acute promyelocytic leukemia"Experimental Hematology. 30. 1273-1282 (2002)
• [Publications] Niitsu, N, Honma, Y, Iijima, K, Takagi, T, Higashihara, M, Sawada, U, Okabe-Kado, J.: "Clinical significance of nm23-H1 proteins expressed on cell surface in non-Hodgkin's lymphoma"Leukemia. 17. 196-202 (2003)
• [Publications] Nakamaki, T, Okabe-Kado, J, Yamamoto-Yamaguchi, Y, Hino, K, Tomoyasu, S, Honma, Y, Kasukabe, T.: "Role of MmTRA1b/phospholipid scramblase 1 gene expression in the induction of differentiation of human myeloid leukemia cells into granulocytes"Experimental Hematology. 30. 421-429 (2002)
• [Publications] Honma, Y: "Cotylenin A, a plant growth regulator, as a differentiation-inducing agent against myeloid leukemia"Leukemia & Lymphoma. 43. 1169-1178 (2002)
• [Publications] Honma, Y, Ishii, Y.: "Differentiation of human myeloid leukemia cells by plant redifferentiation-inducing hormones"Leukemia & Lymphoma. 43. 1729-1735 (2002)
• [Publications] Honma, Y: "Induction of differentiation of human myeloid leukemia cells by novel synthetic neurotrophic pyrimidine derivatives"Exp Hematol. 29. 194-201 (2001)
• [Publications] Niitsu, N: "Sensitization by 5-aza-2'-deoxycytidine of leukaemia cells with MLL abnormalities to induction of differentiation by all-trans retinoic acid and 1α,25-dihydroxyvitamin D_3"Br J Haematol. 112. 315-326 (2001)
• [Publications] Yamamoto-Yamaguchi, Y: "Induction of the monocytic differentiation of myeloid leukaemia cells by cotylenin A,a plant growth regulator"Br J Haematol. 112. 697-705 (2001)
• [Publications] Yamamoto-Yamaguchi, Y: "Inducton of differentiation of human myeloid leukemia cells by immunosuppresant macrolides(rapamycin and FK506)and calcium/calmodulin-dependent kinase inhibitors"Exp Hematol,. 29. 582-588 (2001)
• [Publications] Kano, Y: "In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents"Blood. 97. 1999-2007 (2001)
• [Publications] Niitsu, N: "Serum nm23-H1 protein as a prognostic factor in aggressive non-Hodgkin's lymphoma"Blood. 97. 1202-1210 (2001)
• [Publications] Niitsy,N,Ishii,Y,Matsuda,A,Honma,Y: "Induction of differentiation of acute promyelocytic leukemia cells by a cylidine deaminase-resistant analog of cytosine arabinoside, 1-(2-deoxy-2-methylene-β-D-erythro-pentofuranosyl) cytidine."Cancer Res. 61. 178-185 (2001)
• [Publications] Niitsu,N,Kasukabe,T,Yokoyama,A,Okabe-Kado,J,Yamamoto-Yamaguchi,Y,Umeda,M,Honma,Y: "Anticancer derivative of butyric acid (pivalyloxymethyl butyrate) specifically potentiates the cytotoxicity of doxoiubicin and daunorubicin through the suppression of microsomal glycosidic acitivity."Mol Pharmacol. 58. 27-36 (2000)
• [Publications] Niitsy,N,Okabe-Kado,J,Nakayama,M,Wakimoto,N,Sakashita,A,Maseki,N,Motoyoshi,K,Umeda,M,Honma,Y.: "Plasma levels of the differentiation inhibitory factor nm23-H1 protein and their clinical implication in acute myelogenous leukemia."Blood. 96. 1080-1086 (2000)
• [Publications] Niitsu,N,Yamamoto-Yamaguchi,Y,Kasukabe,T,Okabe-Kado,J,Umeda,M,Honma,Y.: "Antileukemic efficacy of 2'-deoxycoformycin in monocytic leukemia cells."Blood. 96. 1512-1516 (2000)
• [Publications] Niitsu,N,Hayashi,Y,Honma,Y.: "Downregulation of MLL-CBP fusion gene expression is associated with differentiation of SN-1 cells with t (11;16)(q23;p13)."Oncogene. 20. 375-384 (2001)
• [Publications] Hayashi,Y,Honma,Y,Niitsu,N,Taki,T,Bessho,F,Sako,M,Mori,T,Yanagisawa,M,Tsuji,K,Nakahata,T: "SN-1, a novel leukemic cell line with t (11;16)(q23;p13) : Myeloid characteristics and resistance to retinoids and vitamin D3."Cancer Res. 60. 1139-1145 (2000)